Journal of Critical Care (2012) 27, 744.e7–744.e15

Circuit lifespan during continuous renal replacementtherapy for combined liver and kidney failure☆,☆☆,★

Horng-Ruey Chua MBBSa,d, Ian Baldwin PhDa,b, Michael Bailey MD c,Ashwin Subramaniam MBBS a, Rinaldo Bellomo MDa,c,⁎

aDepartment of Intensive Care, Austin Hospital, Melbourne, AustraliabRMIT University, School of Nursing and Health Sciences, Melbourne, AustraliacAustralian and New Zealand Intensive Care Research Committee (ANZIC-RC), Monash University, School of Public Healthand Preventive Medicine, Melbourne, AustraliadDivision of Nephrology, UniversityMedicineCluster, NationalUniversityHospital, NationalUniversity Health System, Singapore

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5

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Keywords:Acute liver failure;Acute kidney injury;Bleeding risk;Circuit life;Cirrhosis;Continuous renalreplacement therapy;

Decompensated chronicliver disease;

No anticoagulation;Thrombocytopenia

AbstractPurpose: To evaluate circuit lifespan (CL) and bleeding risk during continuous renal replacementtherapy (CRRT), in combined liver and renal failure.Methods: Single-center retrospective analysis of adults with acute liver failure or decompensatedcirrhosis who received CRRT, without anticoagulation or with heparinization in intensive care unit.Results: Seventy-one patients with 539 CRRT circuits were evaluated. Median overall CL was 9 (6–16)hours. CL was 12 (7-24) hours in 51 patients never anticoagulated for CRRT. In 20 patients whosubsequently received heparinization, CL was 7 (5-11) hours without anticoagulation, which did notimprove with systemic or regional heparinization (P = .231), despite higher peri-circuit activated partialthromboplastin time (APTT) and heparin dose. Using multivariate linear regression, patients with higherbaseline APTT or serum bilirubin, or who were not mechanically ventilated, had longer CL (P b .05).Additionally, peri-circuit thrombocytopenia (P b .0001) or higher international normalized ratio (P b.05) predicted longer CL. Of 71 patients, 33 had significant bleeding events. Using multivariate logisticregression, patients with higher baseline APTT, vasoactive drug use N24 hours, or thrombocytopenia,had more bleeding complications (P b .05). Decreasing platelet counts (especially b50 × 109/mm3) hadan incremental effect on CL (P b .0001).Conclusion: CRRT CL is short in patients with liver failure despite apparent coagulopathy.Thrombocytopenia predicts longer CL and bleeding complications.© 2012 Elsevier Inc. All rights reserved.

☆ The authors confirm that the results presented in this paper have not been published previously in whole or part, except in abstract form.☆☆ Disclosures/Conflicts of Interest. The authors have no conflicts of interest to declare.★ Contributions: HRC, IB, and RB conceived the study idea and proposal, and developed the study design. HRC, IB, and AS collected the data. HRC, MB,

nd RB analyzed the data. HRC and RB wrote the manuscript. All authors were involved in the revision of the manuscript, and take responsibility of the data ande contents of the article.⁎ Corresponding author. Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), Melbourne, Victoria 3181, Australia. Tel.: +61 3 9496

992; fax: +61 3 9496 3932.E-mail address: rinaldo.bellomo@austin.org.au (R. Bellomo).

883-9441/$ – see front matter © 2012 Elsevier Inc. All rights reserved.ttp://dx.doi.org/10.1016/j.jcrc.2012.08.016

744.e8 H.R. Chua et al.

1. Introduction

Liver failure is associated with bleeding, sepsis, vasodi-latory shock, multi-organ dysfunction [1], and acute kidneyinjury (AKI). The incidence of AKI is 29% in advancedcirrhosis and 33% in liver failure needing transplantation[2,3]. AKI is also a predictor of short and long-termmortality in this cohort [2,4,5]. The dual impact of renal andhepatic dysfunction is especially significant, due to frequentneed for blood products and difficulties with metabolic andvolume control. Thus, renal replacement therapy (RRT) isoften indicated.

Continuous RRT (CRRT) is the preferred option for RRTin these patients because it reduces the risk of cerebral edema[6,7]. However, frequent circuit clotting may compromisetreatment efficacy [8] and lead to blood loss, which increasesthe need for transfusion [9]. The use of systemic or regionalanticoagulation is restricted by bleeding tendencies, lack ofsafety data in liver failure, and concerns about impairedhepatic clearance of citrate [10,11]. Accordingly, in manypatients, CRRT is managed with no anticoagulation. Theimpact of this approach on circuit lifespan (CL) has not beenwell studied.

Therefore, we aimed to investigate CRRT circuitlongevity in critically ill patients with liver failure andAKI, and the incidence of bleeding complications duringtherapy. Additionally, we evaluated the ability of hemato-logical and coagulation parameters to predict either bleedingor longer CL. We hypothesized that CL would be short andbleeding events frequent and that both would be predicted bythrombocytopenia and coagulation tests.

2. Methods

2.1. Study design and population

The study was conducted in a regional tertiary referralcenter for patients with liver failure in possible need foremergent transplantation. We retrospectively studied criticallyill patients aged N18 years, diagnosed with acute liver failure(ALF) or decompensated chronic liver disease (DCLD)complicated by AKI (class “failure” by RIFLE classification)[12], who were admitted to the intensive care unit (ICU) andreceived CRRT from January 2006 till July 2011.

Patients were identified using the ICU admissiondatabase. CRRT circuits were studied until cessation oftherapy, patient death, ICU discharge, or liver transplanta-tion. CRRT circuits used during and after liver transplantwere excluded. In addition, we excluded circuits terminatedprematurely due to elective indications (patient transports forscans or procedures, planned cessation, renal recovery, andwithdrawal of artificial life support). The study was approvedby the Human Research Ethics Committee, which waived theneed for informed consent.

2.2. Definitions and data collection

We included patients diagnosed with ALF, with aninternational normalized ratio (INR) of at least 1.5 duringhospitalization and any degree of hepatic encephalopathy[13,14]. Chronic liver disease was defined as presence ofhistologic or ultrasonographic evidence of hepatic cirrhosis.DCLD was inferred by presence of related complicationsincluding variceal bleeding, symptomatic ascites, encepha-lopathy, or bacterial peritonitis, which required hospitaliza-tion [15]. The ICU admission diagnosis was the acutecondition that precipitated need for intensive care. Patients’profile, laboratory investigation results, and illness severityindices on ICU admission were collected. Specifically, wecomputed the model for end-stage liver disease (MELD)score to reflect the severity of liver disease [16,17].Clinically significant bleeding complications that warrantedmedical intervention and blood transfusions were identified.

In addition, patients’ hemoglobin levels, platelet counts,INR and activated partial thromboplastin time (APTT) wereobtained from levels performed just prior to, or within 12hours of each circuit commencement; so as to reflect thecurrent hematological profile peri-CRRT circuit. If unavail-able, corresponding results on the day of every circuitcommencement were used.

2.3. CRRT details

All patients received either continuous venovenous hemo-filtration or hemodiafiltration (CVVH or CVVHDF). Hemo-diafilter membranes were of AN69 polyacrylonitrile orpolyamide with surface area of 1.2 m2 or greater (Gambro,Lund, Sweden). Blood pump rate was set at 200 mL/minroutinely. Replacement fluid was administered as 50% to 50%or 70% to 30% in pre- and post-dilutional modes for CVVH,respectively; and 100% post-dilution for CVVHDF. Replace-ment fluid and dialysate flowwere divided in equal proportionsfor CVVHDF. Systemic heparinization for CRRT wasachieved by pre-filter heparin infusion with no reversal,while regional heparinization included post-filter infusion ofprotamine, with ratio of heparin 100 IU to protamine 1 mg.

The prescribed CRRT dose was calculated for individualcircuits using the documented effluent rate and estimatedbody weight. Details on anticoagulation (including dose)were collected.

2.4. Data analysis

Statistical analysis was performed using SAS version 9.2(SAS Institute Inc, Cary, NC). Parametric variables werepresented as mean (±S.D.) and compared using Studentt test, whereas non-parametric variables were presented asmedian (interquartile range) and compared using Mann-Whitney or Kruskal-Wallis test. Categorical variables werepresented as frequency (percentage) and compared using

744.e9CRRT circuit life in liver failure

χ2 or Fisher exact test. The CL was found to be wellapproximated by a log-normal distribution and was log-transformed prior to analysis. Univariate and multivariateanalysis of CL were performed using mixed linear modelingwith individual patients treated as random effects. Allavailable variables were considered for inclusion into themultivariate model for CL life (see Table 3), with the finalmodel developed using both stepwise selection and back-wards elimination techniques with the P value for inclusioninto the final model being .05. The final model was assessedfor collinearity and plausibility using correlation coefficientsand the difference in parameter estimates and standard errors

Table 1 Profile of study population

Patient characteristics All patients

n = 71

Age, mean (SD), y 45.9 (11.2)Male sex, no. (%) 26 (36.6)Primary etiology of liver diseaseAlcohol-induced, no. (%) 10 (14.1)Hepatitis virus, no. (%) 15 (21.1)Drug-induced, no. (%) 26 (36.6)Metabolic disease, no. (%) 7 (9.9)Autoimmune/biliary disease, no. (%) 5 (7.0)Others, no. (%) 8 (11.3)Reason for ICU admission, no. (%)Severe encephalopathy 37 (52.1)Hepatorenal syndrome 13 (18.3)Septic shock 12 (16.9)Acute pulmonary edema 5 (7.0)Other hemodynamic shock 4 (5.6)Illness severity scores on ICU admissionAPACHE III score, mean (SD) 100 (30)MELD score, mean (SD) 37 (8)Admission serum laboratory resultsHemoglobin, mean (SD), g/dL 10.3 (2.5)Platelet count, mean (SD) 132 (76)INR, median (IQR) 2.7 (2.0-4.2)APTT, mean (SD) 58 (30)Albumin, mean (SD), g/L 29 (13)Bilirubin, median (IQR), μmol/L 160 (82-385)Renal function upon CRRT commencementUrea, median (IQR), mmol/L 11.8 (6.5-25.6)Creatinine, mean (SD), μmol/L 296 (162)Progression in ICU and hospitalMechanical ventilation, no. (%) 56 (78.9)MV duration, median (IQR), h 75 (20-240)Vasoactive drugs N24 h, no. (%) 49 (69.0)CRRT duration, median (IQR), d 5 (3-8)Bleeding complications, no. (%) 33 (46.5)ICU LOS, median (IQR), d 8 (5-17)Hospital LOS, median (IQR), d 17 (9-36)Liver transplant, no. (%) 13 (18.3)ICU mortality, no. (%) 30 (42.3)Hospital mortality, no. (%) 34 (47.9)

APACHE, Acute Physiology and Chronic Health Evaluation; IQR, interquartile

between univariate and multivariate models. Multivariateanalysis of bleeding complications was performed usinglogistic regression with both stepwise selection and back-wards elimination techniques considering all plausiblevariables (see Table 4). The criteria for inclusion into thefinal model was P = .05. Goodness of fit was determinedusing a Hosmer and Lemeshow Goodness-of-Fit Test whilediscrimination was determined using area under the curve.Kaplan-Meier plots and log-rank test were used to furtherassess differential effects of peri-circuit variable(s) on circuitlifespan. A 2-sided P value of .05 was considered to bestatistically significant.

ALF DCLD P

n = 41 n = 30

44.2 (11.6) 48.3 (10.3) .9311 (26.8) 15 (50.0) .045

1 (2.4) 9 (30.0) .0019 (22.0) 6 (20.0) .8426 (63.4) 0 (0) b.0010 (0) 7 (23.3) .0021 (2.4) 4 (13.3) .164 (9.8) 4 (13.3) .71

26 (63.4) 11 (36.7) .039 (22.0) 4 (13.3) .545 (12.2) 7 (23.3) .221 (2.4) 4 (13.3) .160 (0) 4 (13.3) .03

100 (34) 101 (24) .5537 (9) 38 (8) .70

11.4 (2.4) 8.8 (1.9) b.0001142 (84) 117 (63) .083.9 (2.4-5.2) 2.2 (1.8-2.8) .000157 (31) 59 (30) .6229 (16) 30 (7) .63112 (74-193) 428 (160-595) b.0001

7.8 (5.3-10.3) 25.4 (14.2-37.4) b.0001284 (176) 313 (142) .77

33 (80.5) 23 (76.7) .70131 (24-308) 38 (10-117) .0526 (63.4) 23 (76.7) .234 (3-8) 5 (3-12) .7717 (41.5) 16 (53.3) .328 (4-16) 8 (6-19) .4714 (8-22) 22 (13-54) .026 (14.6) 7 (23.3) .3520 (48.8) 10 (33.3) .1920 (48.8) 14 (46.7) .86

range; LOS, length of stay; MV, mechanical ventilation.

744.e10 H.R. Chua et al.

3. Results

We studied 71 patients, of whom 41(57.7%) had ALF and30 (42.3%) had DCLD (Table 1). For patients with ALF, theadmission platelet counts, INR, and APTT were 142(±84) ×109/mm3, 3.9 (2.4-5.2) and 57(±31) seconds, respectively,while corresponding levels for patients with DCLD were117(±63) × 109/mm3, 2.2 (1.8-2.8), and 59 (±30) seconds. Asignificantly higher proportion of patients with ALF werewomen with drug-related hepatotoxicity as predominantdisease etiology. Patients with ALF were also more likely topresent with severe encephalopathy and higher INR on ICUadmission, whereas patients with DCLD had lower admissionhemoglobin, higher initial serum bilirubin levels, and longerhospitalization. Their illness severity indices such as AcutePhysiology and Chronic Health Evaluation (APACHE) IIIand MELD scores were comparable (Table 1).

Data were collected on 631 circuits. Ninety-two circuitswere terminated due to elective indications andwere excluded.Analysis was performed on the remaining 539 (85.4%)circuits. The overall median CL was 9 (6-16) hours; 503 of539 circuits (93%) were performed via femoral venous access.In patients never anticoagulated for CRRT (n = 51), medianCL was 12 (7-24) hours, with median 1.0 (0.6-1.4) circuitchange per CRRT day. In patients who subsequently receivedheparinization for CRRT (n = 20), median circuit change was

Table 2 CRRT circuit profile

Circuit characteristics ALL circuits Circuits of patients wno AC throughout a

n = 539 n = 230

Circuit lifespan, median(IQR), h

9.0 (6.0-15.5) 12.0 (7.0-24.0)

CVVH/CVVHDF, No. 330/209 160/70Vascular access, No. (%)Femoral vein 503 (93.3) 196 (85.2)Internal jugular/subclavianvein

36 (6.7) 34 (14.8)

Prescribed intensity, median(IQR), mL/kg per h

32.8 (22.2-50.0)

30.8 (24.1-40.0)

Heparin dose, median (IQR),U/kg per h

NA 0 (0)

Circuit hematology profile c

Hemoglobin, median (IQR),g/dL

8.1 (7.4-9.3) 8.1 (7.3-9.1)

Platelet count, median (IQR) 49 (32-84) 51 (34-97)INR, median (IQR) 2.3 (1.8-3.0) 2.3 (1.9-3.0)APTT, median (IQR),seconds

46 (38-57) 48 (40-61)

AC, anticoagulation; IQR, interquartile range; NA, not applicable.a Circuits of patients who were never anticoagulated throughout for CRRTb Circuits of patients who were not anticoagulated initially, but subsequentlc Hematology results obtained before each circuit or during initial hours frod Comparing only results of last 3 columns.

more frequent at 1.5 (1.1-1.9) per CRRT day compared to theformer (P = .001); and median CL was 7 (5-11) hours withoutanticoagulation; which did not improve significantly withsystemic or regional heparinization (P = .231). This wasdespite significantly elevated systemic APTT with systemicheparinization, higher intravenous heparin dose with regionalheparinization, and greater proportion of circuits performedusing hemodiafiltration versus hemofiltration (Table 2). Nopatients received regional citrate anticoagulation.

Fifty-one patients never anticoagulated during CRRTwere transfused a median of 0.63 (0.20-1.20) U of packedred blood cell (PRBC) per CRRT day, or 1 unit PRBCevery 1.6 days; as compared to 0.38 (0-0.74) U of PRBCper CRRT day or 1 unit every 2.6 days, in patientssubsequently anticoagulated during CRRT (P = .10).Among the latter 20 patients, the respective amounts ofPRBC per CRRT day received during anticoagulation-freeversus heparinized CRRT, were 0.40 (0-0.93) versus 0.17(0-0.61) U; with median difference of zero (95% confidenceinterval [CI] 0-0.40) U.

On multivariate linear regression analysis, longer CL wasassociated with higher APTT and serum bilirubin levels onICU admission, as well as lower peri-CRRT circuit plateletcounts. The absence of mechanical ventilation during ICUstay and higher INR were not significantly associated withlonger CL on univariate comparison but became statistically

ith Circuits of patients with no AC initially,but with subsequent AC b

P d

InitialAC free

Systemicheparin

Regionalheparin

n = 188 n = 29 n = 92

7.0 (5.0-10.5) 7.5 (5.0-13.0) 8.0 (5.8-12.0) .23

112/76 10/19 48/44 .03

186 (98.9) 29 (100.0) 92 (100.0) NA2 (1.1) 0 (0) 0 (0)

40.0 (22.2-50.0) 28.6 (22.2-50.0) 31.0 (22.2-51.7) .66

0 (0) 6.4 (5.8-8.3) 13.9 (11.1-17.2) 0.0001

8.3 (7.6-9.4) 7.6 (7.4-8.6) 8.0 (7.3-9.9) .20

45 (29-67) 58 (45-76) 47 (30-84) .042.2 (1.7-2.9) 2.5 (1.6-2.9) 2.2 (1.8-3.1) .5943 (37-52) 64 (40-87) 47 (37-56) .001

(51 patients).y received heparin for CRRT (20 patients).m each circuit commencement.

Fig. 1 Kaplan-Meier analysis of circuit lifespan by differentialcircuit platelet count and INR. Platelet counts are expressed as×109/mm3.

744.e11CRRT circuit life in liver failure

significant on multivariate analysis (Table 3). ALF/DCLDwas removed from the multivariate model due to collinearitywith other more significant variables, namely admissionbilirubin (ρ = 0.5), vasoactive drugs N24 hours (ρ = 0.3), andmechanical ventilation (ρ = 0.4).

Decreasing platelet count had an incremental effect on CL(P b .0001, log-rank test). Median CLs for platelet count ofb50, versus 50 to b80, versus ≥80 × 109/mm3; were 11.0(7.0-21.0) versus 8.0 (5.5-13.5) versus 7.0 (5.0-11.0) hours,respectively (Fig. 1).

Of 71 patients, 33 (46.5%) had bleeding complications,including 27 who were never anticoagulated for CRRT. Ofthese 33 patients, 18 (54.6%) had gastrointestinal bleedingwith 11 who underwent urgent endoscopy. Etiologiesinclude variceal bleed, portal gastropathy, and hemorrhoids;13 (39.4%) patients had severe bleeding from line sitesincluding 3 with arterial bleed; 9 had severe orifice bleedingsuch as epistaxis or mucosal bleed; and 3 had intra-abdominal bleeding.

On multivariate logistic regression analysis, patients withhigher APTT at ICU admission, prolonged use ofvasoactive drugs N24 hours, and lower median peri-circuitplatelet counts had more bleeding complications duringICU stay (Table 4). The respective amounts of PRBC perCRRT day received by patients who had bleedingcomplications versus none were 0.88 (0.63-1.25) versus0.08 (0-0.50) U (P b .0001).

Table 3 Predictors of longer circuit lifespan—linear regression models

Variables Univariate analysis Multivariate analysis

Estimate SE Probability Estimate SE Probability

Admission hemoglobin −0.032 0.026 .22Admission platelet count −0.001 0.001 .12Admission INR −0.007 0.036 .84Admission APTT 0.008 0.002 .001 0.005 0.002 .03Admission albumin −0.021 0.012 .08Admission bilirubin 0.001 0.0003 .009 0.001 0.0003 .006MELD score 0.007 0.009 .43Pre-CRRT urea 0.003 0.005 .58Pre-CRRT creatinine 0.00002 0.0005 .96Vasoactive drugs N24 h 0.318 0.151 .04Mechanical ventilation −0.167 0.175 .34 −0.447 0.149 .003APACHE III score −0.004 0.003 .15MV duration 0.0004 0.0003 .17Modality (CVVH/CVVHDF) −0.150 0.105 .15Femoral vascular access −0.186 0.165 .26Prescribed CRRT dose −0.007 0.004 .12Heparinization 0.065 0.048 .17Heparin dose 0.002 0.007 .78Circuit hemoglobin −0.040 0.024 .10Circuit platelet count −0.004 0.001 b.0001 −0.005 0.001 b.0001Circuit INR 0.044 0.028 .12 0.068 0.027 .01Circuit APTT 0.004 0.001 .006

MV, mechanical ventilation.

Table 4 Predictors of bleeding complications—logistic regression model ⁎

Variables Univariate analysis Multivariate analysis

Odds ratio (95% CI) Probability Odds ratio (95% CI) Probability

ALF vs DCLD 1.61 (0.62-4.17) .32Admission hemoglobin 0.92 (0.76-1.11) .40Admission platelet count 0.98 (0.97-0.99) .0004Admission INR 1.11 (0.87-1.40) .40Admission APTT 1.06 (1.02-1.10) .002 1.06 (1.01-1.11) .02Admission albumin 0.96 (0.89-1.04) .33Admission bilirubin 1.00 (1.00-1.01) .008MELD score 1.11 (1.04-1.20) .002Pre-CRRT urea 0.99 (0.96-1.03) .66Pre-CRRT creatinine 1.00 (1.00-1.00) .51Vasoactive drugs N24 h 17.22 (3.60-82.39) .0004 8.48 (1.41-51.00) .02Mechanical ventilation 2.95 (0.84-10.40) .09APACHE III score 1.01 (1.00-1.03) .11% Circuits with heparinization 0.14 (0.02-1.05) .06% Circuits with CVVHDF vs CVVH 0.77 (0.26-2.27) .64Median circuit platelet count 0.98 (0.96-0.99) .001 0.98 (0.97-1.00) .02Median circuit INR 1.26 (0.87-1.82) .23Median circuit APTT 1.04 (1.01-1.08) .02

⁎ Hosmer Lemeshow goodness of fit test: P = .77; area under the curve = 0.87.

744.e12 H.R. Chua et al.

4. Discussion

4.1. Statement of key findings

We studied CRRT circuit longevity and bleeding risk inpatients with AKI associated with ALF or DCLD, in whommost circuits were not anticoagulated due to coagulopathy.We found that overall CL was short, and did not improvesignificantly with heparinization. Thrombocytopenia was akey predictor of both longer CL and bleeding complications,whereas conventional coagulation parameters such asderanged INR had only a weak association with longer CL,but not bleeding risk. Other patient-specific predictors oflonger CL include higher admission APTT and serumbilirubin levels, and absence of mechanical ventilation;while higher admission APTT and prolonged vasoactivedrug use predicted bleeding complications. As expected,patients who suffered bleeding complications had signifi-cantly more PRBC transfusions, compared to those who hadno bleeding issues.

4.2. Relationship to other studies

CRRT CL with and without anticoagulation in high-riskpatients had been evaluated in limited studies. Only one dealtspecifically with liver failure. In that study, mean CL forpatients with ALF and DCLD was only 10 to 11 hours,despite seemingly lower baseline platelet counts and worsecoagulation profile than in our study cohort [18]. Decreasingplatelet count also did not predict circuit survival in thatstudy. However, only the baseline hematology results

(before initiation of CRRT) and not respective levels withevery circuit were examined; and only the first three circuitswere assessed. By factoring every platelet count duringcircuit commencement, we have highlighted the independentassociation of thrombocytopenia with prolonged CL.

Thrombocytopenia in liver disease is multifactorial[19,20]. Reduced and dysfunctional platelets may lead toless aggregation and subsequent impaired coagulation;consistent with our findings that thrombocytopenia predictslonger CL and bleeding risk. However, high levels of vonWillebrand factor and its reduced inhibition from ADAMTS13 deficiency can restore platelet function [21,22], whichmay explain our observation that CL was only moresignificantly increased with platelet counts b50 × 109/mm3.

The improved CL from 7 to 11 hours with severethrombocytopenia implies a 50% increase in circuit life.However, in patients never anticoagulated for CRRT, CL of 12hours is still low compared to similar high-risk cohorts, whoreportedly achieved life spans of 19 to 32 hours withoutanticoagulation [23-26]. “High risk for anticoagulation” duringCRRT is conventionally identified by elevated INR, APTT, orthrombocytopenia. Patients with liver disease frequently meetthese criteria. Our study, however, demonstrates that CL ispoor in such patients and challenges the paradigm that CRRTcircuits should run efficiently in patients with liver failure, whoare deemed to be “auto-anticoagulated”.

In contrast, conventional baseline and peri-circuit coag-ulation profiles were not consistent in predicting both longerCL and bleeding risk (with exception of higher baselineAPTT, which probably reflected underlying illness severity).These findings are in agreement with recent evidence thatpatients with liver disease have a parallel decrease in both

744.e13CRRT circuit life in liver failure

procoagulant and anticoagulant factors, but elevated factorVIII and von Willebrand factor, leading to imbalance inhemostasis, which can tip towards either a hypo- orhypercoagulable situation [27-31]. Furthermore, such reduc-tion in circulating coagulants is more severe in ALF thancirrhosis [31] and is worsened by a hypofibrinolytic statefrom increased plasminogen-activator inhibitor levels [32].Rebalanced hemostasis in these patients makes it extremelydifficult to have a predictable or consistent bleeding risk[29]. Moreover, INR is standardized based on a differentreference population receiving a vitamin K antagonist but notvalidated in liver disease [30]. Routine prothrombin time andAPTT assays do not incorporate the action of thrombomo-dulin, which otherwise down-regulates thrombin generationthrough activated protein C and, thus, provide a biasedassessment of procoagulant deficiency, and not anticoagu-lant deficiency [30,33]. These tests also do not assess effectof fibrinolytic factors. These observations explain theinconsistent performance of such tests in predicting CLand bleeding complications in our study.

In addition to the above considerations, CL in our patientswas not improved with heparinization, despite heparin doseup to 14 IU/kg per hour for regional heparinization andoptimal to high systemic APTT of 64 seconds with systemicheparinization [34]. The paradoxical finding that patientswith circuits anticoagulated tend to instead have shorter CLsprobably reflected higher clotting tendencies, whichprompted clinicians to initiate heparinization (Table 2).Yet, this further demonstrates the limited effect of hepar-inization in prolonging circuits in these patients. As thesystemic APTT was prolonged with heparinization, suchpoor efficacy cannot be solely attributed to anti-thrombin IIIdeficiency. Instead, these results might suggest that in-vitrothrombin inhibition with standard test reagents may notreflect actual in-vivo anticoagulant deficiency (such asprotein C) in liver disease. More importantly, heparin cancause thrombocytopenia through reduction in plateletactivation threshold, increased platelet aggregation andsplenic sequestration, and more uncommonly, immune-mediated thrombocytopenia [35]. Given that thrombocyto-penia is prevalent in our patients and is an independentpredictor of bleeding complications, heparinization forCRRT in this cohort may not be justifiable.

Higher baseline serum bilirubin inferred more severeunderlying hepatic failure, which explains the link to betterCL and bleeding risk. The significance of mechanicalventilation on shorter CL is unclear, and may signify theimpact of severe critical illness on a more procoagulant state,mediated by surge in proinflammatory cytokines, plateletactivation and enhanced tissue factor expression [36]. It mayalso affect vascular catheter blood flows due to variations inintrathoracic pressure, though majority of our cohort usedfemoral venous access. On the other hand, prolongedvasoactive drug use, hemodynamic shock, and bleeding/hemorrhage are likely inter-related as cause or effect, thusexplaining the link between the former and latter.

4.3. Significance of study findings

Our study suggests the need to reconsider strategies toimprove CRRT CL in patients with significant liverimpairment. It is reasonable to start with anticoagulation-free circuits for safety concern, especially with severethrombocytopenia, which predicts bleeding complicationsand longer CL. On the other hand, deranged coagulationassays alone do not necessarily imply severe bleedingdiathesis. Regional heparinization appears to add littleclinical benefit. Alternatives such as prostacyclin en-hances CL compared to heparin [37] but may inducemore hypotension, may reduce cerebral perfusion pres-sure in patients with fulminant hepatic failure [38], andis expensive.

Citrate metabolism is impaired in liver disease, and thereappears to be a stepwise increase in citrate toxicity risk inpatients with higher MELD scores [39]. Yet, there isemerging data of acceptable safety profile for up to 60hours of regional citrate anticoagulation in liver patients onextracorporeal circulation, and this may be a viable option inselected patients [40]. In essence, the need for antic-oagulation must be reviewed regularly, in view of progres-sive decrease in platelet count with consecutive circuits andbleeding risk. Finally, thromboelastography may provide abetter assessment of hemostasis during extracorporealcirculation in liver failure [41].

4.4. Strengths and limitations

We have analyzed 539 CRRT circuits, the majority ofwhich were not anticoagulated, making this the largeststudy so far of circuit characteristics in high-risk patientswith liver failure. We accounted for the effect of changinghematology profile on circuit life by studying therespective indices for every circuit. The findings appearlogical, plausible, and consistent with recent literature.Despite the retrospective design, elapsed hours of circuitand downtime were clearly documented routinely in ournursing charts. However, circuit APTT was not measuredfor regional heparinization, and we cannot excludeinadequate anticoagulation as reason for poor efficacy,though the systemic APTT was already 47 seconds in thesepatients. There may be interpretation bias in assessingreasons for premature circuit termination. The vast majorityof patients had femoral venous access, and hence, theseresults are less applicable for patients with alternativevascular access. The CRRT circuit profiles of patients withALF and DCLD were pooled and analyzed together,despite likely differences in their thrombogenic milieu. Wecannot comment on the effect of diffusive or convectivetherapies on CL as the respective CRRT intensity was notcontrolled for. We are also unable to account for effects ofplasma or platelet transfusion on circuit clotting. Our studyis single center in nature and requires confirmation in otherhealthcare systems.

744.e14 H.R. Chua et al.

5. Conclusions

In conclusion, CRRT CL without anticoagulation in high-risk patients with significant liver impairment is generallyshort despite apparent coagulopathy and is not improvedsignificantly by circuit heparinization. Severe thrombocyto-penia is strongly associated with longer CL and bleedingcomplications, while conventional coagulation assays areinconsistent in predicting impaired hemostasis. This high-lights the need for further studies to determine improvedtechniques to assess hemostasis in this unique patient cohort,and alternative strategies to optimize CRRT circuit longevitywithout compromising patient safety.

Acknowledgments

Dr Horng-Ruey Chua was a recipient of the SingaporeHealthcare Manpower Development Program award in 2010,which was co-funded by the Ministry of Health Singapore,and National University Health System Singapore. The fundswere utilized for his clinical and research training in AustinHealth, Melbourne, Australia.

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